Abstract

Combined administration of methotrexate (MTX) and non-steroidal anti-inflammatory drugs (NSAIDs) can result in a decreased systemic clearance of MTX. To date, inhibition of renal uptake via OATs and efflux via MRPs by NSAIDs has been recognized as the possible sites of drug interaction between MTX and NSAIDs. Although most NSAIDs are glucuronized in kidney tissue and excreted mainly as glucuronide conjugates, it is not fully known whether the glucuronides of NSAIDs (NSAIDs-Glu) inhibit MTX excretion via MRP2 and MRP4. The purpose of this study was to investigate the inhibitory effects of the glucuronides of several NSAIDs (diclofenac, R- and S-ibuprofen, R- and S-flurbiprofen and R- and S-naproxen) as well as parent NSAIDs on MTX uptake using human MRP2- and MRP4-expressing inside-out vesicles. Results confirm that all NSAIDs and NSAIDs-Glu examined exhibited stereoselective and concentration-dependent inhibitory effects on MTX uptake via MRP2 and MRP4. Notably, NSAIDs-Glu potently inhibited MTX uptake via MRP2 and MRP4 compared with the corresponding parent NSAIDs except for naproxen in MRP2 and S-flurbiprofen in MRP4. Furthermore, higher inhibitory effects of S-isomers on MRP2-mediated MTX uptake were observed compared with their antipodes, and on the contrary, MRP4-mediated MTX uptake was more susceptible to the inhibition by R-isomers. The present results suggest that the glucuronides of NSAIDs are likely to be involved in the inhibition of urinary excretion of MTX via MRP2 and MRP4 in addition to parent NSAIDs.